Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: design, synthesis, inhibitory activity and 3D-QSAR analysis

Zhong-Chang Wang; Ya-Juan Qin; Peng-Fei Wang; Yong-An Yang; Qing Wen; Xin Zhang; Han-Yue Qiu; Yong-Tao Duan; Yan-Ting Wang; Ya-Li Sang; Hai-Liang Zhu

doi:10.1016/j.ejmech.2013.04.035

Sulfonamides containing coumarin moieties selectively and potently inhibit carbonic anhydrases II and IX: design, synthesis, inhibitory activity and 3D-QSAR analysis

Eur J Med Chem. 2013 Aug:66:1-11. doi: 10.1016/j.ejmech.2013.04.035. Epub 2013 May 9.

Authors

Zhong-Chang Wang¹, Ya-Juan Qin, Peng-Fei Wang, Yong-An Yang, Qing Wen, Xin Zhang, Han-Yue Qiu, Yong-Tao Duan, Yan-Ting Wang, Ya-Li Sang, Hai-Liang Zhu

Affiliation

¹ State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.

PMID: 23777898
DOI: 10.1016/j.ejmech.2013.04.035

Abstract

A series of sulfonamides containing coumarin moieties had been prepared that showed a very interesting profile for the inhibition of two human carbonic anhydrase inhibitors. These compounds were evaluated for their ability to inhibit the enzymatic activity of the physiologically dominant isozymes hCA II and the tumor-associated isozyme hCA IX. The most potent inhibitor against hCA II and IX were compounds 5d (IC₅₀ = 23 nM) and 5l (IC₅₀ = 24 nM), respectively. These sulfonamides containing coumarin moieties may prove interesting lead candidates to target tumor-associated CA isozymes, wherein the CA domain is located extracellularly. Eighteen compounds were scrutinized by CoMFA and CoMSIA techniques of 3D quantitative structure-activity relationship. Nine of the compounds were evaluated for cytotoxicity against human macrophage.

Keywords: 3D-QSAR; Antitumor activity; CCK-8 assay; Carbonic anhydrase; Sulfonamide derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Apoptosis / drug effects
Carbonic Anhydrase II / antagonists & inhibitors*
Carbonic Anhydrase II / chemistry
Carbonic Anhydrase II / metabolism
Carbonic Anhydrase IV / antagonists & inhibitors*
Carbonic Anhydrase IV / chemistry
Carbonic Anhydrase IV / metabolism
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrase Inhibitors / pharmacology
Chemistry Techniques, Synthetic
Coumarins / chemical synthesis
Coumarins / chemistry*
Coumarins / metabolism
Coumarins / pharmacology*
Drug Design*
Humans
Isoenzymes / antagonists & inhibitors
Isoenzymes / chemistry
Isoenzymes / metabolism
MCF-7 Cells
Melanoma, Experimental
Molecular Docking Simulation
Protein Conformation
Quantitative Structure-Activity Relationship*
Substrate Specificity
Sulfonamides / chemistry*

Substances

Antineoplastic Agents
Carbonic Anhydrase Inhibitors
Coumarins
Isoenzymes
Sulfonamides
coumarin
Carbonic Anhydrase II
Carbonic Anhydrase IV